Diclofenac/ Misoprostol

Registered South African indications: 

• Osteoarthritis 
• Rheumatoid arthritis 
• Prophylaxis of non-steroidal anti-inflammatory-induced gastric and duodenal ulceration

Contraindications

• Hypersensitivity to the active ingredients or any of the excipients in this combination product
• Hypersensitivity to acetylsalicylic acid
• Hypersensitivity to other non-steroidal anti-inflammatory drugs 
• Hypersensitivity to other prostaglandins
• Pregnancy
• Breastfeeding
• Severe renal impairment 
• Severe hepatic impairment 
• Active peptic ulcer 
• Perforated peptic ulcer 
• Active bleeding 
• Peri-operative pain in the setting of coronary artery bypass graft surgery
• Congestive cardiac failure (NYHA II-IV)
• Ischemic heart disease
• Peripheral arterial disease
• Cerebrovascular disease

Cautions 

• Mild to moderate renal impairment 
• Mild to moderate hepatic impairment 
• Elderly
• Pre-menopausal women
• High doses
• Severe dehydration
• Congestive cardiac failure (NYHA I)
• Cirrhosis 
• Hypertension
• Hyperlipidaemia
• Diabetes mellitus
• Smoking
• Inflammatory bowel disease
• Haematopoietic disorders or conditions with defective coagulation
• Bronchial asthma
• Allergic disease
• Long-term therapy 
• Galactose intolerance
• Lapp lactase deficiency
• Glucose-galactose malabsorption

Forms avail. in SA and covered in this monograph: tab 

Osteoarthritis 
Rheumatoid arthritis 
Prophylaxis of non-steroidal anti-inflammatory-induced gastric and duodenal ulceration

Diclofenac/ Misoprostol
50mg/200μg

• Oral (tab): 1 tab, 8-12hrly

75mg/200μg

• Oral (tab): 1 tab, 12hrly

---

Take with food 

---

Do not cut/crush/chew/dissolve

Not established for use in children below 18 years

Pregnancy 

• Contraindicated Diclofenac / Misoprostolis (75mg / 200mcg) 
• Misoprostol: 
  • Misoprostol induces uterine contractions and is associated with abortion, premature birth, foetal death, and foetal malformations. Approximately a 3-fold increased risk of malformations was reported in pregnancies exposed to misoprostol during the first trimester, compared to a control group incidence of 2%
  • In particular, prenatal exposure  to misoprostol has been associated with Moebius syndrome (congenital facial paralysis leading to hypomimia, troubles of suckling and deglutition and eye movements, with or without limb defects); amniotic band syndrome (limb deformities/amputations, especially clubfoot, acheiria, olygodactyly, cleft palate inter alia) and central nervous system anomalies (cerebral and cranial anomalies such as acencephaly, hydrocephaly, cerebellar hypoplasia, neural tube defects)
  • Other defects including arthrogryposis have been observed
  • Women should be informed of the risk of teratogenicity
  • Should the patient wish to continue with her pregnancy after exposure of misoprostol in utero, a careful ultrasound scan monitoring of the pregnancy, with special attention to the limbs and head must be carried out
• Diclofenac:
  • Inhibition of prostaglandin synthesis might adversely affect pregnancy and/or the embryo/foetal development
  • Data from epidemiological studies suggest an increased risk of miscarriage and of cardiac malformation and gastroschisis after use of prostaglandin synthesis inhibitors in early pregnancy. The absolute risk for cardiovascular malformation was increased from less than 1%, up to approximately 1.5%. The risk is believed to increase with dose and duration of therapy
  • In animals, administration of prostaglandin synthesis inhibitors has been shown to result in increased pre- and post-implantation loss and embryo-foetal lethality. In addition, increased incidences of various malformations, including cardiovascular, have been reported in animals given a prostaglandin synthesis inhibitor during the organogenetic period
  • During the third trimester of pregnancy, all prostaglandin synthesis inhibitors may expose the foetus to:
    • Caridopulmonary toxicity (with premature closure of the ductus       arteriosus and pulmonary hypertension);
    • Renal dysfunction, which may progress to renal failure with oligo-       hydroamniosis;
• The mother and the neonate, at the end of pregnancy, to:
  • Possible prolongation of bleeding time, an anti-aggregating effect which may occur even at very low doses;
  • Inhibition of uterine contractions resulting in delayed or prolonged labour

Breastfeeding 

• Contraindicated
• Diclofenac / Misoprostol should not be administered to nursing mothers
• Misoprostol is rapidly metabolised in the mother to misoprostol acid, which is biologically active and is excreted in breast milk
• Diclofenac is excreted in breast milk in very small quantities. In general, the potential effects on the infant from any exposure to misoprostol and its metabolites via breastfeeding are unknown
• However, diarrhoea is a recognised side effect of misoprostol and could occur in infants of nursing mothers

Fertility 

• Based on the mechanism of action, the use of NSAIDs, including diclofenac/misoprostol, may delay or prevent rupture of ovarian follicles, which has been associated with reversible infertility in some women
• In women who have difficulties conceiving or who are undergoing investigation of infertility, withdrawal of NSAIDs, including diclofenac/misoprostol, should be considered
• Women of childbearing potential must be informed about the risk of teratogenicity prior to treatment with diclofenac/misoprostol
• Treatment must not be initiated until pregnancy is excluded, and women should be fully counselled on the importance of adequate contraception while undergoing treatment. If pregnancy is suspected, treatment must be immediately discontinued

Renal Impairment

• Mild to moderate: Caution; no dose adjustment recommended  
• Severe: Contraindicated

Hepatic Impairment

• Mild to moderate: Caution; no dose adjustment recommended  
• Severe: Contraindicated

Elderly

• Caution; no dose adjustment recommended

Porphyria Information

• Probably not porphyrinogenic (PNP)
• Diclofenac: Probably not porphyrinogenic (PNP)
• Misoprostol: Probably not porphyrinogenic (PNP)

Drugs in Sport

• Permitted - No warning

Central Nervous System Disorders

• Headache
• Dizziness
• Cerebrovascular accident
• Seizures 
• Memory disturbance
• Drowsiness
• Tremor
• Paraesthesia
• Aseptic meningitis
• Insomnia
• Nightmares
• Psychotic reaction
• Disorientation
• Depression
• Anxiety
• Mood changes
• Irritability
• Fatigue 

Cardiovascular Disorders

• Myocardial infarction
• Cardiac failure
• Palpitations
• Hypertension
• Shock
• Hypotension
• Vasculitis
• Chest pain 

Respiratory Disorders

• Dyspnoea
• Asthma
• Pneumonitis

Gastrointestinal Disorders

• Abdominal pain
• Diarrhoea
• Nausea and vomiting 
• Dyspepsia
• Gastritis
• Flatulence
• Eructation
• Constipation
• Peptic ulcer
• Gastrointestinal inflammation
• Duodenitis
• Oesophagitis
• Stomatitis
• Gastrointestinal bleeding
• Pancreatitis
• Gastrointestinal perforation
• Colitis
• Oesophageal disorder
• Mouth ulceration
• Glossitis
• Tongue odema
• Dry mouth

Hepatobiliary Disorders

• Hepatitis
• Jaundice
• Hepatic failure
• Fulminant hepatitis
• Increased bilirubin 
• Increased hepatic enzymes 

Genitourinary Disorders

• Vaginal infection
• Renal failure
• Renal papillary necrosis
• Interstitial nephritis
• Nephrotic syndrome
• Proteinuria
• Haematuria
• Glomerulonephritis
• Intra-uterine death
• Uterine rupture
• Incomplete abortion
• Premature baby
• Anaphylactoid syndrome of pregnancy
• Retained placenta or membranes
• Abnormal uterine contractions
• Menorrhagia
• Metrorrhagia
• Vaginal haemorrhage
• Postmenopausal haemorrhage
• Uterine haemorrhage
• Uterine spasm
• Decreased female fertility 
• Breast pain

 Endocrine and Metabolic Disorders

• Anorexia
• Fluid retention
• Breast pain

Skin and Subcutaneous Tissue Disorders

• Pruritus
• Purpura
• Urticaria
• Angioedema
• Bullous dermatitis
• Erythema multiforme
• Toxic epidermal necrolysis
• Stevens-Johnson syndrome
• Exfoliative dermatitis
• Henoch Schonlein purpura
• Mucocutaneous rash
• Vesicular rash 
• Photosensitivity reaction
• Alopecia
• Oedema 

Immune, Blood and Lymphatic System Disorders

• Thrombocytopenia
• Aplastic anaemia
• Agranulocytosis
• Haemolytic anaemia
• Leucopenia
• Inhibition of platelet aggregation
• Anaphylactic reaction
• Hypersensitivity
• Fever 
• Chills 
• Decreased haemoglobin 

Sensory Disorders

• Blurred vision
• Visual disturbances
• Taste disturbances
• Tinnitus

Others 

• Birth defects

• Diuretics
• Potassium-sparing agents
• Ciclosporin
• Tacrolimus
• Lithium
• Digoxin
• Ketoconazole
• Oral antidiabetic agents 
• Oral anticoagulants
• Antiplatelet agents
• Selective serotonin reuptake inhibitors
• Methotrexate
• Corticosteroids
• Angiotensin-converting enzyme inhibitors
• Angiotensin II antagonists
• Beta blockers
• Antacids
• Quinolone antibacterials
• Mifepristone
• CYP2C9 inhibitors

• Full blood count
• Electrolytes
• Hepatic function
• Renal function
• Blood pressure
• Pregnancy test

Specific cases may require

• Ophthalmic examination

Diclofenac
Diclofenac inhibits prostaglandin synthesis by inhibition of cyclooxygenase.

Misoprostol
Misoprostol protects the gastroduodenal mucosa by inhibiting basal, stimulated and nocturnal acid secretion. It also acts by reducing the volume of gastric secretions and the proteolytic activity of the gastric fluid and increasing bicarbonate and mucus secretion. It has also been shown to induce uterine contractions. 

COMBINATION PREPARATIONS

Diclofenac/ Misoprostol

Tablet 50mg/200μg

• Arthrotec 50 (Pfizer) originator

Tablet 75mg/200μg

• Arthrotec 75 (Pfizer) originator